Novel therapies for the treatment of Chikungunya virus (CHIKV) infections are urgently needed to address the alarming spread of this pathogen across the Americas. We have identified a series of potent, selective, and orally bioavailable inhibitors of CHIKV replication. In this Direct to Phase project, we will optimize this series of CHIKV inhibitors to Pre-Development stage and advance a first ever CHIKV antiviral candidate to IND-enabling studies. To accomplish this task, we will execute an integrated medicinal chemistry optimization/biological profiling campaign to optimize the potency, drug-like properties and oral exposure of the series. One or more Pre-Development Candidates will be identified and advanced through candidate selection studies into non-GLP repeat-dose tox in both rats and dogs.